Inhibitors of ion channels

ABSTRACT

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-gated sodium channels. More particularly, the invention provides substituted aryl sulfonamides, compositions comprising these compounds, as well as methods of using these compounds or compositions in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrence of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a voltage-gated sodium channel.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/555,977, which claims priority to U.S. Provisional PatentApplication Ser. No. 60/732,543, filed on Nov. 2, 2005, each of which isherein incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

This invention relates to the use of certain compounds as sodium channelblockers and to the treatment of pain by the inhibition of sodiumchannels. Additionally, this invention relates to novel compounds thatare useful as sodium channel blockers.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels are found in all excitable cells includingmyocytes of muscle and neurons of the central and peripheral nervoussystem. In neuronal cells sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper and appropriatefunction of sodium channels is therefore necessary for normal functionof the neuron. Consequently, aberrant sodium channel function is thoughtto underlie a variety of medical disorders (See Hubner C A, Jentsch T J,Hum. Mol. Genet., 11(20): 2435-45 (2002) for a general review ofinherited ion channel disorders) including epilepsy (Yogeeswari et al.,Curr. Drug Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D., Proc.Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)) myotonia (Cannon, S C,Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, J N et al., J.Neurobiol., 61(1): 55-71 (2004)). See Table I, below.

TABLE I Gene Primary TTX Disease Type Symbol tissue IC-50 associationIndications Na_(v)1.1 SCN1A CNS/PNS 10 Epilepsy Pain, seizures,neurodegeneration Na_(v)1.2 SCN2A CNS 10 Epilepsy Epilepsy,neurodegeneration Na_(v)1.3 SCN3A CNS 15 — Pain Na_(v)1.4 SCN4A Sk.muscle 25 Myotonia Myotonia Na_(v)1.5 SCN5A Heart 2000 ArrhythmiaArrhythmia Na_(v)1.6 SCN8A CNS/PNS 6 — Pain, movement disordersNa_(v)1.7 SCN9A PNS 25 Erythermalgia Pain Na_(v)1.8 SCN10A PNS 50000 —Pain Na_(v)1.9 SCN11A PNS 1000 — Pain

There are currently 10 known members of the family of voltage-gatedsodium channel (VGSC) alpha subunits. Names for this family includeSCNx, SCNAx, and Na_(v)x.x. The VGSC family has been phylogeneticallydivided into two subfamilies Na_(v)1.x (all but SCN6A) and Na_(v)2.x(SCN6A). The Nav1.x subfamily can be functionally subdivided into twogroups, those which are sensitive to blocking by tetrodotoxin(TTX-sensitive or TTX-s) and those which are resistant to blocking bytetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, H1) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and conduction disorders (Liu H, et al., Am. J.Pharmacogenomics, 3(3): 173-9 (2003)). Consequently, blockers of Nav1.5have found clinical utility in treatment of such disorders (Srivatsa U,et al., Curr. Cardiol. Rep., 4(5): 401-10 (2002)). The remainingTTX-resistant sodium channels, Nav1.8 (SCN10A, PN3, SNS) and Nav1.9(SCN11A, NaN, SNS2) are expressed in the peripheral nervous system andshow preferential expression in primary nociceptive neurons. Humangenetic variants of these channels have not been associated with anyinherited clinical disorder. However, aberrant expression of Nav1.8 hasbeen found in the CNS of human multiple sclerosis (MS) patients and alsoin a rodent model of MS (Black, J A, et al., Proc. Natl. Acad. Sci. USA,97(21): 11598-602 (2000)). Evidence for involvement in nociception isboth associative (preferential expression in nociceptive neurons) anddirect (genetic knockout). Nav1.8-null mice exhibited typicalnociceptive behavior in response to acute noxious stimulation but hadsignificant deficits in referred pain and hyperalgesia (Laird J M, etal., J. Neurosci., 22(19):8352-6 (2002)).

The TTX-sensitive subset of voltage-gated sodium channels is expressedin a broader range of tissues than the TTX-resistant channels and hasbeen associated with a variety of human disorders. The Na_(v)1.1 channelwell exemplifies this general pattern, as it is expressed in both thecentral and peripheral nervous system and has been associated withseveral seizure disorders including Generalized Epilepsy with FebrileSeizures Plus, types 1 and 2 (GEFS+1, GEFS+2), Severe Myoclonic Epilepsyof Infancy (SMEI), and others (Claes, L, et al., Am. J. Hum. Genet., 68:1327-1332 (2001); Escayg, A., Am. J. Hum. Genet., 68: 866-873 (2001);Lossin, C, Neuron, 34: 877-884 (2002)). The Nav1.2 channel is largely,if not exclusively, expressed in the central nervous system andquantitative studies indicate it is the most abundant VGSC of the CNS.Mutations of Nav1.2 are also associated with seizure disorders(Berkovic, S. F., et al., Ann. Neurol., 55: 550-557 (2004)) andNav1.2-null “knockout” mice exhibit perinatal lethality (Planells-CasesR et al., Biophys. J., 78(6):2878-91 (2000)). Expression of the Nav1.4gene is largely restricted to skeletal muscle and, accordingly,mutations of this gene are associated with a variety of movementdisorders (Ptacek, L. J., Am. J. Hum. Genet., 49: 851-854 (1991); HudsonA J, Brain, 118(2): 547-63 (1995)). The majority of these disorders arerelated to hyperactivity or “gain-of-function” and have been found torespond to treatment with sodium channel blockers (Desaphy J F, et al.,J. Physiol., 554(2): 321-34 (2004)).

Neither the SCN3A nor the SCN8A VGSC genes have been conclusively linkedto heritable disorders in humans. Loss-of-function mutations of theSCN8A gene are known in mice and yield increasingly debilitatingphenotypes, dependent upon the remaining functionality of the geneproducts (Meisler M H, Genetica, 122(1): 37-45 (2004)). Homozygous nullmutations cause progressive motor neuron failure leading to paralysisand death, while heterozygous null animals are asymptomatic. Homozygousmed^(J) mice have nearly 90% reduction in functional Nav1.6 current andexhibit dystonia and muscle weakness but are still viable. Evidence forNav1.6 being important for nociception is largely associative as Nav1.6is expressed at high levels in dorsal root ganglia and can be found inspinal sensory tracts (Tzoumaka E, J. Neurosci. Res., 60(1): 37-44(2000)). It should be noted however that expression of Nav1.6 is notrestricted to sensory neurons of the periphery. Like the Nav1.6 channel,expression of the Nav1.3 VGSC can also be detected in both the centraland peripheral nervous system, though levels in the adult CNS aregenerally much higher than PNS. During development and the earlypostnatal period Nav1.3 is expressed in peripheral neurons but thisexpression wanes as the animal matures (Shah B S, Physiol., 534(3):763-76 (2001); Schaller K L, Cerebellum, 2(1): 2-9 (2003)). Followingneuronal insult Nav1.3 expression is upregulated, more closely mimickingthe developmental expression patterns (Hains B C, J. Neurosci., 23(26):8881-92 (2003)). Coincident with the recurrence of Nav1.3 expression isthe emergence of a rapidly re-priming sodium current in the injuredaxons with a biophysical profile similar to Nav1.3 (Leffler A, et al.,J. Neurophysiol., 88(2): 650-8 (2002)). Treatment of injured axons withhigh levels of GDNF has been shown to diminish the rapidly reprimingsodium current and reverses thermal and mechanical pain-relatedbehaviors in a rat model of nerve injury, presumably by down-regulatingthe expression of Nav1.3 (Boucher T J, Curr. Opin. Pharmacol., 1(1):66-72 (2001)). Specific down-regulation of Nav1.3 via treatment withantisense oligonucleotides has also been shown to reverse pain-relatedbehaviors following spinal cord injury (Hains B C, J. Neurosci., 23(26):8881-92 (2003)).

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA, 94(4): 1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 may play a keyrole in various pain states, including acute, inflammatory and/orneuropathic pain. Deletion of the SCN9A gene in nociceptive neurons ofmice led to a reduction in mechanical and thermal pain thresholds andreduction or abolition of inflammatory pain responses (Nassar et al.,Proc Natl Acad Sci USA, 101(34): 12706-11 (2004)). In humans, Na_(v)1.7protein has been shown to accumulate in neuromas, particularly painfulneuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144(8): 803-10(2002)). Mutations of Na_(v)1.7, both familial and sporadic, have alsobeen linked to primary erythermalgia, a disease characterized by burningpain and inflammation of the extremities (Yang et al., J. Med. Genet.,41(3): 171-4 (2004)). Congruent with this observation is the report thatthe non-selective sodium channel blockers lidocaine and mexiletine canprovide symptomatic relief in cases of familial erythermalgia(Legroux-Crepel et al., Ann. Dermatol Venereol., 130: 429-433).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics and in the treatment of cardiac arrhythmias. It hasalso been reported that sodium channel-blocking agents may be useful inthe treatment of pain, including acute, chronic, inflammatory and/orneuropathic pain; see, for example, Wood, J N et al., J. Neurobiol.,61(1): 55-71 (2004). Preclinical evidence demonstrates that sodiumchannel-blocking agents can suppress neuronal firing in peripheral andcentral sensory neurons, and it is via this mechanism that they may beuseful for relieving pain. In some instances abnormal or ectopic firingcan originate from injured or otherwise sensitized neurons. For example,it has been shown that sodium channels can accumulate in peripheralnerves at sites of axonal injury and may function as generators ofectopic firing (Devor et al. J. Neurosci., 132: 1976 (1993)). Changes insodium channel expression and excitability have also been shown inanimal models of inflammatory pain where treatment with proinflammatorymaterials (CFA, Carrageenan) promoted pain-related behaviors andcorrelated with increased expression of sodium channel subunits (Gouldet al., Brain Res., 824(2): 296-9 (1999); Black et al., Pain, 108(3):237-47 (2004)). Alterations in either the level of expression ordistribution of sodium channels, therefore, may have a major influenceon neuronal excitability and pain-related behaviors.

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies and resistance or insensitivity to opiates iscommon. In addition, many of the currently available treatments haveundesirable side effects. It has been reported that there is notreatment to prevent the development of neuropathic pain or to controlestablished neuropathic pain. Mannion et al., Lancet, 353: 1959-1964(1999).

Ohkawa et al. have described a class of cyclic ethers that are of use assodium channel blockers (U.S. Pat. No. 6,172,085).

Currently, gabapentin is the principal treatment for neuropathic pain.As with epilepsy, its mechanism of action for pain is unknown. However,as little as only 30% of patients respond to gabapentin treatment forneuropathic pain.

In view of the limited number of agents presently available and the lowlevels of efficacy of the available agents, there is a pressing need forcompounds that are potent, specific inhibitors of ion channelsimplicated in neuropathic pain. The present invention provides suchcompounds, methods of using them, and compositions that include thecompounds.

SUMMARY OF THE INVENTION

It has now been discovered that various substituted aryl sulfonamidesare potent modulators of sodium channels. In the discussion thatfollows, the invention is exemplified by reference to the inhibition ofsodium channels that are localized in the peripheral nervous system, andin particular those compounds that are selective inhibitors of TTX-ssodium channels, and are useful for treating pain through the inhibitionof sodium ion flux through channels that include a TTX-s sodium channelsubunit. The compounds, compositions and methods of the presentinvention are useful for treating diseases in which modulating one ormore TTX-s sodium channels provides relief from the disease. Ofparticular interest is the use of the compounds, compositions andmethods of the invention for treating pain and central or peripheralnervous system disorders, preferably peripheral nervous systemdisorders. The present invention is of use for treating acute, chronic,inflammatory, and/or neuropathic pain.

The present invention provides compounds that are useful in thetreatment of diseases through the modulation of sodium ion flux throughvoltage-dependent sodium channels. More particularly, the inventionprovides compounds, compositions and methods that are useful inameliorating or alleviating conditions susceptible to such ion channelmodulation as more fully described below.

In a first aspect, the invention provides a compound according toFormula I:

In this formula, R¹, R², R³ and R⁴ are independently selected from H, F,CF₃, substituted or unsubstituted C₁-C₄ alkyl, unsubstituted 4- to7-membered cycloalkyl and unsubstituted 4- to 7-memberedheterocycloalkyl.

The symbol A represents a member selected from:

R⁵ is selected from C₁-C₄ substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. R⁶and R^(6′) are independently selected from H, C₁-C₄ substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. R⁵ and R⁶ are optionally joined to form amember selected from a substituted or unsubstituted cycloalkyl moiety ora substituted or unsubstituted heterocycloalkyl moiety.

The symbol B represents a member selected from:

The symbol X represents a member selected from O and S.

The symbol Y represents a member selected from CH and N. The index srepresents an integer greater than 0, sufficient to satisfy the valencerequirements of the ring atoms. Each R⁷ is independently selected fromH, OR⁸, NR⁹R¹⁰, SO₂NR⁹R¹⁰, cyano, halogen, CF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. R⁸ is selected from H, CF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. R⁹ and R¹⁰ are independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. In an exemplary embodiment, sis 1 and R⁷ is a member selected from chloro and fluoro. In an exemplaryembodiment, s is 2 and each R⁷ is a member independently selected fromchloro and fluoro. In an exemplary embodiment, s is 2 and each R⁷ isfluoro. In an exemplary embodiment, B is a member selected from

The symbol Z is a member selected from:

Each R¹¹ is a member independently selected from H, OR¹³, NR¹⁴R¹⁵,SO₂NR¹⁴R¹⁵, cyano, halogen, CF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. R¹³is a member selected from H, CF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. R¹⁴and R¹⁵ are independently selected from H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl. R¹⁴ and R¹⁵, together with the nitrogen to which they arebound, can be optionally joined to form a substituted or unsubstituted5- to 7-membered ring. The index r represents a member selected from theintegers from 0 to 2. The index p represents a member selected from theintegers from 0 to 1. R¹² is selected from H, C₁-C₄ substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. The indices m and n independently represent aninteger selected from 0 to 2, such that when a member selected from mand n can be greater than 1, each R¹ and R²; R³ and R⁴, respectively,can be independently selected.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and acompound as provided above.

In yet another aspect, the present invention provides a method formodulating the activity of a sodium channel in a subject, comprisingadministering to a subject an amount of a compound as provided abovewhich is sufficient to modulate the activity.

In still another aspect, the present invention provides a method ofameliorating or alleviating a condition in a subject. The condition canbe a member selected from, among others, pain, irritable bowel syndrome,Crohn's disease, epilepsy, seizures multiple sclerosis, bipolardepression and tachyarrhythmias. The method comprises administering tothe subject an amount of a compound of the invention sufficient toameliorate or alleviate said condition.

Additional aspects, advantages and objects of the present invention willbe apparent from the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations

The abbreviations used herein generally have their conventional meaningwithin the chemical and biological arts. For example: CHO, Chinesehamster ovary; EBSS, Earl's Balanced Salt Solution; SDS, sodium dodecylsulfate; Et₃N, triethylamine; MeOH, methanol; and DMSO,dimethylsulfoxide.

Definitions

The term “pain” refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic neuropathy (see, e.g., Harrison's Principles ofInternal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991);Williams et al., J. of Med. Chem. 42: 1481-1485 (1999), herein eachincorporated by reference in their entirety).

“Somatic” pain, as described above, refers to a normal nerve response toa noxious stimulus such as injury or illness, e.g., trauma, burn,infection, inflammation, or disease process such as cancer, and includesboth cutaneous pain (e.g., skin, muscle or joint derived) and visceralpain (e.g., organ derived).

“Neuropathic” pain, as described above, refers to pain resulting frominjury to or chronic changes in peripheral and/or central sensorypathways, where the pain often occurs or persists without an obviousnoxious input.

“Acute pain”, as described above, refers to pain which is marked byshort duration or a sudden onset.

“Chronic pain”, as described above, refers to pain which is marked bylong duration or frequent recurrence.

“Inflammatory pain”, as described above, refers to pain which isproduced as a symptom or a result of inflammation or an immune systemdisorder.

“Visceral pain”, as described above, refers to pain which is located inan internal organ.

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

“Compound of the invention,” as used herein refers to the compoundsdiscussed herein, pharmaceutically acceptable salts and prodrugs ofthese compounds.

“Inhibiting” and “blocking,” are used interchangeably herein to refer tothe partial or full blockade of a voltage sodium gated channel by acompound of the invention, which leads to a decrease in ion flux eitherinto or out of a cell in which a voltage-gated sodium channel is found.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents, which would result from writing thestructure from right to left, e.g., —CH₂O— is intended to also recite—OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude, but are not limited to, groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “alkyl,” unlessotherwise noted, is also meant to include those derivatives of alkyldefined in more detail below, such as “heteroalkyl.” Alkyl groups thatare limited to hydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom selected fromthe group consisting of O, N and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S may be placed atany interior position of the heteroalkyl group or at the position atwhich the alkyl group is attached to the remainder of the molecule.Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloallyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloallyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl and heteroaryl groups include phenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituentsfor each of the above noted aryl and heteroaryl ring systems areselected from the group of acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′ R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂ in a numberranging from zero to (2 m′+1), where m′ is the total number of carbonatoms in such radical. R′, R″, R′″ and R″″ each preferably independentlyrefer to hydrogen, substituted or unsubstituted heteroalkyl, substitutedor unsubstituted aryl, e.g., aryl substituted with 1-3 halogens,substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, orarylalkyl groups. When a compound of the invention includes more thanone R group, for example, each of the R groups is independently selectedas are each R′, R″, R′″ and R″″ groups when more than one of thesegroups is present. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 5-, 6-, or7-membered ring. For example, —NR′R″ is meant to include, but not belimited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussionof substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: halogen, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂, —R′, —N₃,—CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′, R″, R′″ and R″″ are preferably independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N)and sulfur (S).

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocyclyl groups.

The term “pharmaceutically acceptable salts” includes salts of theactive compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the present invention containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., Journal of Pharmaceutical Science,66: 1-19 (1977)). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

DESCRIPTION OF THE EMBODIMENTS I. The Compounds

In a first aspect, the invention provides a compound according toFormula I:

In this formula, R¹, R², R³ and R⁴ are members independently selectedfrom H, F, CF₃, substituted or unsubstituted C₁-C₄ alkyl, unsubstituted4- to 7-membered cycloalkyl and unsubstituted 4- to 7-memberedheterocycloalkyl.

The symbol A represents a member selected from:

R⁵ is a member selected from OR*, NR*R**, SR*, —S(O)R*, —S(O)₂R*,—S(O)₂NR*R**, —C(O)R*, —C(O)OR*, —C(O)NR*R**, C₁-C₄ substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. Each R* and R** is a member independentlyselected from substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. Theindex q represents a member selected from the integers from 0 to 2. R⁶and R^(6′) are independently selected from H, C₁-C₄ substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. R⁵ and R⁶ are optionally joined to form amember selected from substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl.

The symbol B represents a member selected from:

The symbol X represents a member selected from O and S.

The symbol Y represents a member selected from CH and N. The index srepresents an integer greater than 0, sufficient to satisfy the valencerequirements of the ring atoms. Each R⁷ is independently selected fromH, OR^(B), NR⁹R¹⁰, SO₂NR⁹R¹⁰, cyano, halogen, CF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. R⁸ is selected from H, CF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. R⁹ and R¹⁰ are members independently selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl.

The symbol Z is selected from:

Each R¹¹ is selected from H, OR¹³, NR¹⁴R¹⁵, SO₂NR¹⁴R¹⁵, cyano, halogen,CF₃, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R¹³ is a member selected fromH, CF₃, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R¹⁴ and R¹⁵ are independentlyselected from H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. R¹⁴ andR¹⁵, together with the nitrogen to which they can be bound, can beoptionally joined to form a substituted or unsubstituted 5- to7-membered ring. The index r represents a member selected from theintegers from 0 to 2. The index p represents a member selected from theintegers from 0 to 1. R¹² is a member selected from C₁-C₄ substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. The indices m and n can independentlyrepresent an integer selected from 0 to 2, such that when a memberselected from m and n can be greater than 1, each R¹ and R²; R³ and R⁴,respectively, can be independently selected.

In an exemplary embodiment, the indices m and n can be 0. In anotherexemplary embodiment, the symbol A is a member selected from

J is a member selected from OR*, NR*R**, SR*, —S(O)R*, —S(O)₂R*,—S(O)₂NR*R**, —C(O)R*, —C(O)OR*, —C(O)NR*R**, C₁-C₄ substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. Each R* and R** is a member independentlyselected from substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. R¹⁸ andR¹⁹ are members independently selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, andsubstituted or unsubstituted aryl. R¹⁸ and R¹⁹, together with eachcarbon to which each of R¹⁸ and R¹⁹ are attached, are optionally joinedto form a member selected from substituted or unsubstituted 3- to7-member cycloalkyl moiety and substituted or unsubstituted 5- to7-member heterocycloalkyl moiety. The index t is an integer selectedfrom 0 to 4, such that when t is greater than 1, each R¹⁸ and R¹⁹ isindependently selected. R⁶ and R¹⁸, together with the atoms to which R⁶and R¹⁸ are attached, are optionally joined to form a substituted orunsubstituted 4- to 7-member heterocycloalkyl moiety. R⁶ and J, togetherwith the atoms to which R⁶ and J are attached, are optionally joined toform a member selected from substituted or unsubstituted 3- to 7-membercycloalkyl moiety and substituted or unsubstituted 5- to 7-memberheterocycloalkyl moiety.

In an exemplary embodiment, J is a member selected from substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyloxy, substituted or unsubstitutedcycloalkylthio, substituted or unsubstituted cycloalkylamino,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkyloxy,substituted or unsubstituted heterocycloalkylthio, substituted orunsubstituted heterocycloalkylamino, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedarylthio, substituted or unsubstituted arylamino, substituted orunsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy,substituted or unsubstituted heteroarylthio, and substituted orunsubstituted heteroarylamino.

In an exemplary embodiment, J is substituted or unsubstituted aryl. Inan exemplary embodiment, J is substituted or unsubstituted phenyl. In anexemplary embodiment, a substituent on the substituted phenyl is amember selected from halogen, methyl, trifluoromethyl, ethyl, t-butyl,methoxy and chlorothienyl. In another exemplary embodiment, substitutedphenyl is a member selected from chlorophenyl, fluorophenyl,dichlorophenyl, difluorophenyl, chlorofluorophenyl,trifluoromethylfluorophenyl, trifluoromethylchlorophenyl,t-butylchlorophenyl, t-butylfluorophenyl, methylchlorophenyl,methylfluorophenyl, methoxychlorophenyl, and methoxyfluorophenyl.

In an exemplary embodiment, J is substituted or unsubstituted aryloxy.In an exemplary embodiment, J is substituted or unsubstituted phenoxy.In an exemplary embodiment, a substituent on the substituted phenoxy isa member selected from halogen, methyl, trifluoromethyl, ethyl, t-butyl,methoxy and chlorothienyl. In another exemplary embodiment, substitutedphenoxy is a member selected from chlorophenoxy, fluorophenoxy,dichlorophenoxy, difluorophenoxy, chlorofluorophenoxy,trifluoromethylfluorophenoxy, trifluoromethylchlorophenoxy,t-butylchlorophenoxy, t-butylfluorophenoxy, methylchlorophenoxy,methylfluorophenoxy, methoxychlorophenoxy, and methoxyfluorophenoxy.

In an exemplary embodiment, J is substituted or unsubstitutedphenylamino. In an exemplary embodiment, a substituent on thesubstituted phenylamino is a member selected from halogen, methyl,trifluoromethyl, ethyl, t-butyl, methoxy and chlorothienyl. In anotherexemplary embodiment, substituted phenylamino is a member selected fromchlorophenylamino, fluorophenylamino, dichlorophenylamino,difluorophenylamino, chlorofluorophenylamino,trifluoromethylfluorophenylamino, trifluoromethylchlorophenylamino,t-butylchlorophenylamino, t-butylfluorophenylamino,methylchlorophenylamino, methylfluorophenylamino,methoxychlorophenylamino, and methoxyfluorophenylamino.

In an exemplary embodiment, J is substituted or unsubstitutedpyridinyloxy. In an exemplary embodiment, J is unsubstitutedpyridinyloxy. In an exemplary embodiment, a substituent on thesubstituted pyridinyloxy is a member selected from halogen, methyl,trifluoromethyl, ethyl, t-butyl, methoxy and chlorothienyl. In anotherexemplary embodiment, substituted pyridinyloxy is a member selected fromchloropyridinyloxy, fluoropyridinyloxy, dichloropyridinyloxy,difluoropyridinyloxy, chlorofluoropyridinyloxy, trifluoromethylfluoropyridinyloxy, trifluoromethylchloropyridinyloxy,t-butylchloropyridinyloxy, t-butylfluoropyridinyloxy,methylchloropyridinyloxy, methylfluoropyridinyloxy,methoxychloropyridinyloxy, and methoxyfluoropyridinyloxy.

In an exemplary embodiment, J is substituted or unsubstitutedbenzo[1,4]dioxin-2-yl. In an exemplary embodiment, J is unsubstitutedbenzo[1,4]dioxin-2-yl. In an exemplary embodiment, a substituent on thesubstituted benzo[1,4]dioxin-2-yl is a member selected from halogen,methyl, trifluoromethyl, ethyl, t-butyl, methoxy and chlorothienyl. Inanother exemplary embodiment, substituted benzo[1,4]dioxin-2-yl is amember selected from chlorobenzo[1,4]dioxin-2-yl,fluorobenzo[1,4]dioxin-2-yl, dichlorobenzo[1,4]dioxin-2-yl,difluorobenzo[1,4]dioxin-2-yl, chlorofluorobenzo[1,4]dioxin-2-yl,trifluoromethylfluorobenzo[1,4]dioxin-2-yl,trifluoromethylchlorobenzo[1,4]dioxin-2-yl,t-butylchlorobenzo[1,4]dioxin-2-yl, t-butylfluorobenzo[1,4]dioxin-2-yl,methylchlorobenzo[1,4]dioxin-2-yl, methylfluorobenzo[1,4]dioxin-2-yl,methoxychlorobenzo[1,4]dioxin-2-yl, andmethoxyfluorobenzo[1,4]dioxin-2-yl.

In an exemplary embodiment, J is substituted or unsubstituted alkyl. Inan exemplary embodiment, J is a member selected from methyl, ethyl,propyl, and 3,3 dimethylbutyl. In an exemplary embodiment, a substituenton the substituted alkyl is a member selected from halogen, methyl,trifluoromethyl, ethyl, t-butyl, methoxy, and chlorothienyl.

In an exemplary embodiment, J is a member selected from

wherein X¹ is a member selected O, S, —NH—, —N(CH₃)—, and a bond.

In an exemplary embodiment, t is 1, R¹⁸ is H and R¹⁹ is H. In anexemplary embodiment, t is 1, R¹⁸ is CH₃ and R¹⁹ is H. In an exemplaryembodiment, t is 1, R¹⁸ is CH₃ and R¹⁹ is CH₃. In an exemplaryembodiment, t is 1, R¹⁸ and R¹⁹, along with the atom to which they areattached, are joined to form a member selected from a cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl ring. In an exemplary embodiment,t is 1, R¹⁸ and R¹⁹, along with the atom to which they are attached, arejoined to form a cyclobutyl ring.

In an exemplary embodiment, t is 2, and each R¹⁸ is H and each R¹⁹ is H.In an exemplary embodiment, t is 2, and at least one R¹⁸ is CH₃ and atleast one R¹⁹ is H. In an exemplary embodiment, t is 2, and at least oneR¹⁸ is CH₃ and at least one R¹⁹ is CH₃. In an exemplary embodiment, t is2, R¹⁸ and R¹⁹, along with the atom to which they are attached, arejoined to form a member selected from a cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl ring. In an exemplary embodiment, t is 2, R¹⁸and R¹⁹, along with the atom to which they are attached, are joined toform a cyclobutyl ring.

In an exemplary embodiment, R⁶ and R¹⁸, together with the atoms to whichR⁶ and R¹⁸ are attached, are joined to form a member selected from asubstituted or unsubstituted azetidinyl, pyrrolidinyl, piperazinyl, orpiperidinyl moiety. In an exemplary embodiment, R⁶ and R¹⁸, togetherwith the atoms to which R⁶ and R¹⁸ are attached, are joined to form anunsubstituted azetidinyl moiety. In an exemplary embodiment, R⁶ and R¹⁸,together with the atoms to which R⁶ and R¹⁸ are attached, are joined toform an unsubstituted piperidinyl moiety.

In an exemplary embodiment, R⁶ and J, together with the atoms to whichR⁶ and J are attached, are joined to form a member selected fromsubstituted or unsubstituted 3- to 7-member cycloalkyl moiety andsubstituted or unsubstituted 5- to 7-member heterocycloalkyl moiety. Inan exemplary embodiment, R⁶ and J, together with the atoms to which R⁶and J are attached, are joined to form a member selected from asubstituted or unsubstituted azetidinyl, pyrrolidinyl, piperazinyl, orpiperidinyl moiety.

In another exemplary embodiment, the symbol A is a member selected from

In another exemplary embodiment, the symbol A is a member selected from

In an exemplary embodiment, R⁶ is CH₃.

In another exemplary embodiment, the compound has a structure accordingto Formulae (II), (Ha), (III) or (IIIa):

R²⁰ and R²¹ are members independently selected from H, OR²², NR²³R²⁴,SO₂NR²³R²⁴, cyano, halogen, CF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. R²²is a member selected from H, CF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. R²³and R²⁴ are members independently selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl.

In an exemplary embodiment, R²⁰ is H and R²¹ is halogen. In an exemplaryembodiment, R²⁰ is halogen and R²¹ is H. In an exemplary embodiment, R²⁰is H and R²¹ is Cl. In an exemplary embodiment, R²⁰ is Cl and R²¹ is H.In an exemplary embodiment, R²⁰ is H and R²¹ is F. In an exemplaryembodiment, R²⁰ is F and R²¹ is H. In an exemplary embodiment, R²⁰ is Cland R²¹ is F. In an exemplary embodiment, R²⁰ is F and R²¹ is F. In anexemplary embodiment, R²⁰ is Cl and R²¹ is Cl.

In another exemplary embodiment, the compound has a structure accordingto Formulae (II), (IIa), (III) or (IIIa) wherein the combination of R²⁰and R²¹ are as described in paragraph 88 and wherein J is a memberselected from a species described in paragraph 71, 72, 73, 74, 75, 76,77, 78 or 79.

In a further exemplary embodiment, the compound has the formula:

wherein R²⁰ and R²¹ are as described above.

In a further exemplary embodiment, the compound has a formula which is amember selected from:

wherein the symbol A is a member selected from

In a further exemplary embodiment, the compound has a formula which is amember selected from:

wherein the symbol A is a member selected from

In another exemplary embodiment, B is a member selected from:

The index s is an integer greater than 0, sufficient to satisfy thevalence requirements of the ring atoms. Each R⁷ is a memberindependently selected from H, OR⁸, NR⁹R¹⁰, SO₂NR⁹R¹⁰, cyano, halogen,CF₃, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R⁸ is a member selected from H,CF₃, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R⁹ and R¹⁰ are membersindependently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl.

In another embodiment, the compound has a formula selected from:

J is a member selected from substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. R¹⁸and R¹⁹ are members independently selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, andsubstituted or unsubstituted aryl. R¹⁸ and R¹⁹, together with eachcarbon to which each of R¹⁸ and R¹⁹ are attached, are optionally joinedto form a member selected from a substituted or unsubstituted 3- to7-member cycloalkyl moiety and substituted or unsubstituted 5- to7-member heterocycloalkyl moiety. The index t is an integer selectedfrom 0 to 4, such that when t is greater than 1, each R¹⁸ and R¹⁹ isindependently selected. R²⁰ and R²¹ are members independently selectedfrom H, OR²², NR²³R²⁴, SO₂NR²³R²⁴, cyano, halogen, CF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. R²² is a member selected from H, CF₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R²³ and R²⁴ are membersindependently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. R²³and R²⁴, together with the nitrogen to which they are bound, areoptionally joined to form a substituted or unsubstituted 5- to7-membered ring.

In an exemplary embodiment, J is a member selected from substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyloxy, substituted or unsubstitutedcycloalkylthio, substituted or unsubstituted cycloalkylamino,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkyloxy,substituted or unsubstituted heterocycloalkylthio, substituted orunsubstituted heterocycloalkylamino, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedarylthio, substituted or unsubstituted arylamino, substituted orunsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy,substituted or unsubstituted heteroarylthio, and substituted orunsubstituted heteroarylamino.

Representative compounds of the invention are set forth in Table II. Inan exemplary embodiment, the compound is a compound set forth in TableII.

Also within the scope of the present invention are compounds of theinvention that are poly- or multi-valent species, including, forexample, species such as dimers, trimers, tetramers and higher homologsof the compounds of the invention or reactive analogues thereof. Thepoly- and multi-valent species can be assembled from a single species ormore than one species of the invention. For example, a dimeric constructcan be “homo-dimeric” or “heterodimeric.” Moreover, poly- andmulti-valent constructs in which a compound of the invention or areactive analogue thereof, can be attached to an oligomeric or polymericframework (e.g., polylysine, dextran, hydroxyethyl starch and the like)are within the scope of the present invention. The framework ispreferably polyfunctional (i.e. having an array of reactive sites forattaching compounds of the invention). Moreover, the framework can bederivatized with a single species of the invention or more than onespecies of the invention.

Moreover, the present invention includes compounds within a motifdescribed herein, which are functionalized to afford compounds havingwater-solubility that is enhanced relative to analogous compounds thatare not similarly functionalized. Thus, any of the substituents setforth herein can be replaced with analogous radicals that have enhancedwater solubility. For example, it is within the scope of the inventionto, for example, replace a hydroxyl group with a diol, or an amine witha quaternary amine, hydroxy amine or similar more water-soluble moiety.In a preferred embodiment, additional water solubility is imparted bysubstitution at a site not essential for the activity towards the ionchannel of the compounds set forth herein with a moiety that enhancesthe water solubility of the parent compounds. Methods of enhancing thewater-solubility of organic compounds are known in the art. Such methodsinclude, but are not limited to, functionalizing an organic nucleus witha permanently charged moiety, e.g., quaternary ammonium, or a group thatis charged at a physiologically relevant pH, e.g. carboxylic acid,amine. Other methods include, appending to the organic nucleus hydroxyl-or amine-containing groups, e.g. alcohols, polyols, polyethers, and thelike. Representative examples include, but are not limited to,polylysine, polyethyleneimine, poly(ethyleneglycol) andpoly(propyleneglycol). Suitable functionalization chemistries andstrategies for these compounds are known in the art. See, for example,Dunn, R. L., et al., Eds. Polymeric Drugs and Drug Delivery Systems, ACSSymposium Series Vol. 469, American Chemical Society, Washington, D.C.1991.

In a second aspect, the invention provides a pharmaceutical formulationcomprising a compound according a formula described herein. In anexemplary embodiment, the invention provides a pharmaceuticalformulation comprising a compound described herein. In an exemplaryembodiment, the invention provides a pharmaceutical formulationcomprising a compound according to Formula I.

In a third aspect, the invention provides a method of modulating theactivity of a sodium channel in a subject. This method comprisesadministering to a subject an amount of a compound according a formuladescribed herein sufficient to modulate said activity. In an exemplaryembodiment, the method comprises administering to a subject an amount ofa compound described herein sufficient to modulate said activity. Thismethod comprises administering to a subject an amount of a compoundaccording a formula described herein sufficient to modulate saidactivity. In an exemplary embodiment, the method comprises administeringto a subject an amount of a compound according to Formula I sufficientto modulate said activity. Methods of detecting and amplifyingmodulation of a sodium channel are generally known in the art. Arepresentative method is set forth in Section III, herein.

In a fourth aspect, the invention provides a method of ameliorating oralleviating a condition in a subject. The condition can be a memberselected from pain, irritable bowel syndrome, Crohn's disease, epilepsy,seizures multiple sclerosis, bipolar depression and tachy-arrhythmias.The method includes administering to the subject an amount of thecompound described herein sufficient to ameliorate or alleviate thecondition. In an exemplary embodiment, the condition is pain, and thepain can be a member selected from acute pain, chronic pain, visceralpain, inflammatory pain and neuropathic pain. Exemplary aspects of thismethod are described in greater detail in section VI, herein.

II. Preparation of the Compounds

Compounds of the present invention can be prepared using readilyavailable starting materials or known intermediates. The syntheticschemes set forth below provide exemplary synthetic pathways for thepreparation of compounds of the invention.

II.a. General Procedure for Synthesizing Sulfamide-Containing Compounds

i)

Sulfamide-containing compounds of the invention can be synthesized asshown in Scheme A.

In this scheme, 1 is reacted with 2 in pyridine, forming 3. Compound 3is next reacted with an amine-containing species such as ammonia inorder to produce substituted amino aryl sulfonamide 4. In some instancescompound 4 can also be purchased from commercial sources or preparedfrom commercially available starting materials, such as aryl amines.

Compound 5 was synthesized by reacting 4 with 2-bromoethanol andchlorosulfonyl isocyanate. Compound 7 was formed by the reaction of anappropriately substituted amine 6 with substituted amino arylsulfonamide 5 in an organic solvent, such as acetonitrile, in thepresence of pyridine or triethylamine at an elevated temperature, e.g.,90° C.

ii.)

The synthesis of compounds of general formulae 7 can also be achieved asoutlined in Scheme B.

Oxazolidinone 8 was synthesized by reacting amine 6 with the product ofthe reaction of 2-bromoethanol and chlorosulfonyl isocyanate in thepresence of a base such as triethylamine. The reaction of theoxazolidinone 8 with 4 provides 7.

II.c. General Procedure for Synthesizing Sulfonamide-ContainingCompounds

Sulfonamide-containing compounds of the invention can be synthesized asshown in scheme C.

A typical procedure for the synthesis of 10 involved the reaction of asulfonyl chloride 9 with an amine 6 in the presence of a base such astriethyl amine. The sulfonyl chloride 9 was prepared by reacting asubstituted aryl amine 4 with NaNO₂ in the presence of CuCl₂ followed byreaction with sulfur dioxide.

III. Assays for Blockers of Voltage-Dependent TTX-Sensitive SodiumChannels

The activity of sodium channels can be assessed using a variety of invitro assays, including but not limited to, measuring ion flux,measuring transmembrane potential, and/or measuring ionic current.Measurement of ionic fluxes can be accomplished by measuring changes inthe concentration of the permeant species or by tracking the movement ofsmall amounts of an appropriately permeant radioactive tracer.Transmembrane potential can be assessed with voltage-sensitivefluorescent dyes or, more sensitively, with electrophysiologicalmethods.

Determination of the effectiveness of compounds as ex vivo blockers ofsodium channels can be assessed by the inhibition of compound actionpotential propagation in isolated nerve preparations (Kourtney andStricharz, LOCAL ANESTHETICS, Springer-Verlag, New York, 1987). A numberof experimental models in the rat are appropriate for assessing the invivo efficacy of the compounds of the invention. For example, theneuropathic pain model produced by the tight ligation of spinal nerves,described by Kim et al., Pain, 50: 355-363 (1992), can be used toexperimentally determine the effect of the compounds of the invention inan in vivo model of pain. Mechanical sensitivity can also be assessedusing a procedure described by Chaplan et al., J. Neurosci. Methods, 53:55-63 (1994). Other assays of use are known to those of skill in theart.

Modulators of TTX-sensitive sodium channels can be tested usingbiologically active recombinant channels, or naturally occurringTTX-sensitive sodium channels, or by using native cells, like neuronsexpressing a TTX-sensitive sodium current. TTX-sensitive sodium channelscan be isolated, co-expressed or expressed in a cell, or expressed in amembrane derived from a cell. In such assays, TTX-sensitive sodiumchannels are generally expressed alone to form a homomeric sodiumchannel or may be co-expressed with a second subunit (e.g., an auxiliarybeta subunit) so as to form a heteromeric sodium channel. TheTTX-sensitive sodium channels are stably expressed in HEK-293 cells, anexample of an effective mammalian expression system.

Modulation can be tested using one of the in vitro or in vivo assaysdescribed above. Samples or assays that are treated with a potentialsodium channel inhibitor are compared to control samples without thetest compound, to examine the extent of modulation. Control samples(untreated with inhibitors) are assigned a relative sodium channelactivity value of 100. Inhibition of TTX-sensitive sodium channels isachieved when the sodium channel activity value relative to the controlis less than 70%, preferably less than 40% and still more preferably,less than 30%. Compounds that decrease the flux of ions will cause adetectable decrease in the ion current density by decreasing theprobability of a TTX-sensitive sodium channel being open, by decreasingconductance through the channel, decreasing the number of channels, ordecreasing the expression of channels.

Changes in ion flux may be assessed by determining changes inpolarization (i.e., electrical potential) of the cell or membraneexpressing the sodium channel. A preferred means to determine changes incellular polarization is by measuring changes in current or voltage withthe voltage-clamp and patch-clamp techniques, using the “cell-attached”mode, the “inside-out” mode, the “outside-out” mode, the “perforatedpatch” mode, the “whole cell” mode or other means of controlling ormeasuring changes in transmembrane potential (see, e.g., Ackerman etal., New Engl. J. Med., 336: 1575-1595 (1997)). Whole cell currents areconveniently determined using the standard methodology (see, e.g.,Hamill et al., Pflugers. Archiv. 391: 85 (1981). Other known assaysinclude: radiotracer flux assays and fluorescence assays usingvoltage-sensitive dyes (see, e.g., Vestergarrd-Bogind et al., J.Membrane Biol. 88: 67-75 (1988); Daniel et al., J. Pharmacol. Meth. 25:185-193 (1991); Holevinsky et al., J. Membrane Biology 137: 59-70(1994)). Assays for compounds capable of inhibiting or increasing sodiumflux through the channel proteins can be performed by application of thecompounds to a bath solution in contact with and comprising cells havinga channel of the present invention (see, e.g., Blatz et al., Nature 323:718-720 (1986); Park, 0.1 Physiol. 481: 555-570 (1994)). Generally, thecompounds to be tested are present in the range from about 1 nM to about100 mM, preferably from about 1 nM to about 30 μM. In an exemplaryembodiment, the compounds to be tested are present in the range fromabout 1 nM to about 3 μM.

The effects of the test compounds upon the function of the channels canbe measured by changes in the electrical currents or ionic flux or bythe consequences of changes in currents and flux. Changes in electricalcurrent or ionic flux are measured by either increases or decreases influx of ions such as sodium or guanidinium ions (see U.S. Pat. No.5,688,830). The cations can be measured in a variety of standard ways.They can be measured directly by concentration changes of the ions orindirectly by membrane potential or by using radioactive ions.Consequences of the test compound on ion flux can be quite varied.Accordingly, any suitable physiological change can be used to assess theinfluence of a test compound on the channels of this invention. Theeffects of a test compound can be measured by a toxin-binding assay.When the functional consequences are determined using intact cells oranimals, one can also measure a variety of effects such as transmitterrelease, hormone release, transcriptional changes to both known anduncharacterized genetic markers, changes in cell metabolism such as cellgrowth or pH changes, and changes in intracellular second messengerssuch as Ca²⁺, or cyclic nucleotides.

High throughput screening (HTS) is of use in identifying promisingcandidate compounds of the invention. Physiologically, sodium channelsopen and close on a millisecond timescale. To overcome the short time inwhich channels are open the HTS assay can be run in the presence of anagent that modifies the gating of the channel, (e.g., pyrethroids,alpha-scorpion toxins, beta-scorpion toxins, batrachotoxin, etc). Theseagents modify the gating of sodium channels and keep the pore open forextended periods of time. In addition, while sodium channels areprimarily selective for sodium, other ionic species can permeate thechannel.

The specificity and effect of the TTX-sensitive sodium channel blockingagents of the invention can also be assayed against non-specificblockers of sodium channels, such as tetracaine, mexilitine, andflecamide.

IV. Pharmaceutical Compositions of VGSC Inhibitors

In another aspect, the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and acompound of the invention described herein.

Formulation of the Compounds (Compositions)

The compounds of the present invention can be prepared and administeredin a wide variety of oral, parenteral and topical dosage forms. Thus,the compounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds described herein can be administered by inhalation, forexample, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. Accordingly, the presentinvention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and either a compounddescribed herein, or a pharmaceutically acceptable salt of a compounddescribed herein.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as pocketed tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

V. Methods for Inhibiting Ion Flow in VGSC

In yet another aspect, the present invention provides methods fordecreasing ion flow through voltage gated sodium channels in a cell,comprising contacting a cell containing the target ion channels with asodium channel-inhibiting amount of a compound described herein.

The methods provided in this aspect of the invention are useful for thediagnosis of conditions that can be treated by inhibiting ion fluxthrough voltage gated sodium channels, or for determining if a patientwill be responsive to therapeutic agents, which act by inhibiting sodiumchannels.

VI. Methods for Treating Conditions Mediated by VGSC

In still another aspect, the present invention provides a method for thetreatment of a disorder or condition through inhibition of a voltagegated sodium channel. In this method, a subject in need of suchtreatment is administered an effective amount of a compound describedherein and/or according to a formula described herein. In a preferredembodiment, the compounds provided herein are used to treat a disorderor condition by inhibiting an ion channel of the VGSC family.

The compounds provided herein are useful as sodium channel inhibitorsand find therapeutic utility via inhibition of VGSCs in the treatment ofdiseases or conditions. The sodium channels that are typically inhibitedare described herein as VGSCs such as the Na_(v)1.1 channel.

The compounds of the invention are particularly preferred for use in thetreating, preventing or ameliorating pain or seizures. The methodincludes administering to a patient in need of such treatment, atherapeutically effective amount of a compound described herein and/oraccording to a formula described herein, or a pharmaceuticallyacceptable salt thereof.

The compounds, compositions and methods of the present invention are ofparticular use in treating pain, including both inflammatory andneuropathic pain. Exemplary forms of pain treated by a compound of theinvention include, postoperative pain, osteoarthritis pain, painassociated with metastatic cancer, neuropathy secondary to metastaticinflammation, trigeminal neuralgia, glossopharangyl neuralgia, adiposisdolorosa, burn pain, acute herpetic and postherpetic neuralgia, diabeticneuropathy, causalgia, brachial plexus avulsion, occipital neuralgia,reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain,burn pain, pain following stroke, thalamic lesions, radiculopathy, andother forms of neuralgic, neuropathic, and idiopathic pain syndromes.

Idiopathic pain is pain of unknown origin, for example, phantom limbpain. Neuropathic pain is generally caused by injury or infection of theperipheral sensory nerves. It includes, but is not limited to pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain is also caused by nerve damage from chronic alcoholism,human immunodeficiency virus infection, hypothyroidism, uremia, orvitamin deficiencies.

Moreover, any VGSC inhibitory substance possessed of satisfactory VGSCmodulating activity coupled with favorable intracranial transferkinetics and metabolic stability is expected to show efficacy in centralnervous system (CNS) diseases and disorders such as central nervoussystem ischemia, central nervous system trauma (e.g. brain trauma,spinal cord injury, whiplash injury, etc.), epilepsy, seizures,neurodegenerative diseases (e.g. amyotrophic lateral sclerosis (ALS),Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabeticneuropathy, etc.), vascular dementia (e.g. multi-infarct dementia,Binswanger's disease, etc.), manic-depressive psychosis, depression,schizophrenia, chronic pain, trigeminal neuralgia, migraine, ataxia,bipolar disorder, spasticity, mood disorders, psychotic disorders,hearing and vision loss, age-related memory loss, learning deficiencies,anxiety and cerebral edema.

In treatment of the above conditions, the compounds utilized in themethod of the invention are administered at the initial dosage of about0.001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.1mg/kg to about 100 mg/kg is more typical. The dosages, however, may bevaried depending upon the requirements of the patient, the severity ofthe condition being treated, and the compound being employed.Determination of the proper dosage for a particular situation is withinthe skill of the practitioner. Generally, treatment is initiated withsmaller dosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention. In the examples below, unless otherwise stated,temperatures are given in degrees Celsius ° C.); operations were carriedout at room or ambient temperature (typically a range of from about18-25° C.; evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (typically, 4.5-30 mmHg) with a bathtemperature of up to 60° C.; the course of reactions was typicallyfollowed by TLC and reaction times are provided for illustration only;melting points are uncorrected; products exhibited satisfactory ¹H-NMRand/or LC/MS data and yields are provided for illustration only. Thefollowing conventional abbreviations are also used: mp (melting point),L (liter(s)), mL (milliliters), mmol (millimoles), g (grams), mg(milligrams), min (minutes), LC-MS (liquid chromatography-massspectrometry) and h (hours), PS (polystyrene), DIE(diisopropylethylamine).

Example 1 1.1 Preparation ofN-(3,4-dichloro-phenyl)-ethyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-sulfamide,7a 1.1.a Preparation ofN,N′-di[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-sulfamide, 5a

Chlorosulfonylisocyanate (3.4 mL, 39 mmol) in methylene chloride (100mL, 2 mol) was cooled to 0° C. and then 2-bromoethanol (2.8 mL, 40 mmol)in methylene chloride (20 mL, 300 mmol) was added dropwise over 30 min.The reaction mixture was stirred for 30 min and concentrated in vacuo.To this residue was added N-(2-thiazolyl)-sulfanilamide (20.4 g, 80mmol), 4a, in pyridine (250 mL). The reaction mixture was heated at 80°C. overnight, cooled to rt and concentrated in vacuo. To this was added1 N HCl (100 mL) and the resulting yellow precipitate was filtered andwashed with chloroform to give crude material 5a (which was used in1.1.b without further purification). MS m/z: 573 (M+1).

1.1.b Preparation ofN-(3,4-dichloro-phenyl)ethyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-sulfamide,7a

To a solution of 5a (1.0 g, 1.75 mmol) in acetonitrile, 20 mL oftriethylamine (1.2 mL, 8.7 mmol) and 3,4-dichlorophenethylamine (0.285mL, 1.92 mmol), 6a, were added. The reaction mixture was heated at 90°C. for 2 h, cooled to rt and concentrated in vacuo. The residue waspartitioned between ethyl acetate and water and the organic solution waswashed with 1 N HCl, brine and then dried with MgSO₄. The crude productwas purified by column chromatography to give 125.6 mg of pure product7a, which was converted to the sodium salt. ¹H NMR (300 MHz, DMSO-d₆): δ9.93 (bs, 1H), 7.69-7.67 (m, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.11-7.08 (m,1H), 7.47 (s, 1H), 7.10 (d, J=8.7 Hz, 2H), 6.91 (d, J=3.9 Hz, 1H), 6.41(d, J=3.9 Hz, 1H), 3.09-3.02 (m, 2H), 2.70-2.65 (m, 2H). MS m/z: 507(M+1).

1.2 Preparation ofN-(3,3-diphenylpropyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-sulfamideNa Salt, 7b

The same procedure was used to prepare 7b, with the exception that3,3-diphenylpropylamine was used in place of 3,4-dichlorophenethylamine.¹H NMR (300 MHz, DMSO-d₆): δ 9.94 (bs, 1H), 7.63 (d, J=8.5 Hz, 2H),7.31-7.11 (m, 10H), 7.06 (d, J=8.7 Hz, 2H), 6.89 (d, J=3.8 Hz, 1H), 6.38(d, J=3.8 Hz, 1H), 3.95 (t, J=7.6 Hz, 1H), 2.75-2.70 (m, 2H), 2.13 (q,J=6.7 Hz, 2H). MS m/z: 529 (M+1).

1.3 Preparation ofN-(trans-2-phenylcyclopropyl)-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-sulfamide,7c

1.3.a Preparation of 2-oxo-oxazolidine-3-sulfonic acid(2-phenyl-cyclopropyl) -amide, 8a

To a round bottom flask was added chlorosulfonyl isocyanate (0.4 mL,4.64 mmol) and methylene chloride (5 mL) under an atmosphere of argon.The mixture was cooled in an ice bath and 2-bromoethanol (0.535 mL, 7.55mmol) in methylene chloride (1 mL) was added dropwise. After stirringfor 30 minutes at 0° C., triethylamine (2.28 mL, 16.4 mmol) andtrans-2-phenylcyclopropylamine hydrochloride (0.867 g, 5.11 mmol), 6a,in methylene chloride (5 mL) was added at such a rate that the reactiontemperature was maintained between 0° C. and 10° C. The resultingsolution was stirred at rt for 5 h and then partitioned between 1N HCland water. The organic layer was dried with sodium sulfate, filtered andconcentrated. The crude was purified by chromatography to give 569 mg ofa waxy solid, 8a. ¹H NMR (300 MHz, DMSO-d₆): δ 7.34-7.22 (m, 3H), 7.12(d, J=7.0 Hz, 2H), 6.00 (s, 1H), 4.50-4.33 (m, 2H), 4.16-3.95 (m, 2H),2.66-2.61 (m, 1H), 2.43-2.37 (m, 1H), 1.48-1.41 (m, 1H), 1.30 (q, J=6.5Hz, 1H). MS m/z: 283 (M+1).

1.3.b Preparation ofN-(trans-2-phenylcyclopropyl)-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-sulfamideNa salt, 7c

Triethylamine (1.2 mL, 8.7 mmol) and N-(2-thiazolyl)-sulfanilamide(0.285 mL, 1.92 mmol), 4b, were added to a solution of2-oxo-oxazolidine-3-sulfonic acid (2-phenyl-cyclopropyl)-amide (0.285mL, 1.92 mmol), 8, in acetonitrile (20 mL). The reaction mixture washeated at 100° C. for 2 h. After cooling to rt, the reaction mixture wasconcentrated in vacuo. The residue was dissolved in ethyl acetate andwashed with 1 N HCl, brine and dried with MgSO₄. The crude was purifiedby column chromatography to give 125.6 mg of 7c. The product wasconverted to its sodium salt. ¹H NMR (300 MHz, DMSO-d₆): δ 10.1 (bs,1H), 7.62 (d, J=8.4 Hz, 2H), 7.38-7.14 (m, 3H), 7.08 (d, J=8.6 Hz, 2H),6.99 (d, J=7.1 Hz, 2H), 6.90 (d, J=3.9 Hz, 1H), 6.39 (d, J=3.9 Hz, 1H),2.41-2.43 (m, 1H), 1.90-1.84 (m, 1H), 1.07 (q, J=5.9 Hz, 2H). MS m/z:451 (M+1).

1.4 Preparation ofN-[(2,2-diphenyl)]ethyl]-N′-{2-[5-(N-thiazol-2-yl-sulfonamyl)-pyridinyl]}-sulfamide,7d

The same procedure was used to prepare compound 7d, with the exceptionthat 6-amino-pyridine-3-sulfonic acid thiaol-2-ylamide was4-(N-thiazol-2-yl-sulfonamyl)-2-pyridinyl]sulfamide used in place of4-(N-thiazol-2-yl-sulfonamyl)]-sulfanilamide and 2,2-diphenylethylaminewas used in place of 3,4-dichlorophenethylamine. ¹H NMR (300 MHz,DMSO-d₆): δ 12.86 (1H, bs), 11.10 (1H, bs), 8.5 (1H, d, J=2.4 Hz), 7.95(1H, dd, J=2.4, 8.7 Hz), 7.53 (1H, t, J=5.5 Hz), 7.11-7.33 (10H, m),6.97 (1H, d, J=8.8 Hz), 6.89 (1H, d, J=4.6 Hz), 4.16-4.24 (1H, m), 3.52(2H, t, J=6.2 Hz). MS m/z: 516 (M+1).

1.5 Preparation ofN-[(3,3-diphenyl)]-propyl]-N′-{5-[5-(N-thiazol-2-yl-sulfonamyl)-pyridinyl]}-sulfamide,7e

The same procedure was used to prepare compound 7e, with the exceptionthat 5-amino-pyridine-2-sulfonic acid thiaol-2-ylamide was used in placeof 6-amino-pyridine-3-sulfonic acid thiaol-2-ylamide and2,2-diphenylethylamine was used in place of 3,4-dichlorophenethylamine.¹H NMR (300 MHz, DMSO-d₆): δ 12.77 (1H, bs), 10.42 (1H, s), 8.34 (1H, d,J=2.5 Hz), 7.89-7.94 (2H, m), 7.63 (1H, dd, J=2.5, 8.6 Hz), 7.11-7.30(10H, m), 6.85 (1H, d, J=4.6 Hz), 3.93 (1H, t, J=7.8 Hz), 2.75 (2H, q,J=6.4 Hz), 2.15 (2H, d, J=7.3 Hz). MS m/z: 530 (M+1).

Example 2 2.1 Preparation of benzene-1,4-disulfonic acid1-[(2,2-diphenylethyl)-amide]4-thiazol-2-ylamide, 10a

2.1.a Preparation of 4-(thiazol-2-ylsulfamoyl)-benzenesulfonyl chloride,9a

To a mixture of N-(2-thiazolyl)-sulfanilamide (1.27 g, 4.97 mmol), 4a,in acetonitrile (40 mL) was added acetic acid (4 mL), followed byconcentrated hydrogen chloride (4 mL). The resulting slurry was cooledto 5° C. and sodium nitrite (0.38 g, 5.5 mmol) in 1 mL of water wasadded over and the mixture was stirred. After 20 min the slurry became aclear orange solution and then SO₂ in acetic acid (10 mL) was addedfollowed by copper (II) chloride (0.67 g, 5.0 mmol) in 1 mL of water.The mixture was stirred for 2 h and the yellow precipitate was filtered,washed with acetonitrile, water, and dried overnight to give the desiredproduct 9a as a yellow solid. MS m/z: 339 (M+1).

2.1.b Preparation of benzene-1,4-disulfonic acid1-[(2,2-diphenyl-ethyl)-amide]4-thiazol-2-ylamide, 10a

To a vial was added 4-(thiazol-2-ylsulfamoyl)-benzenesulfonyl chloride9a (0.105 g, 0.3 mmol), pyridine (1 mL), and 2,2-diphenyl-ethylamine(0.0640 g, 0.3 mmol). The reaction was stirred overnight and thenconcentrated. The crude product was purified by chromatography to givedesired compound 10a. MS m/z: 500 (M+1).

2.2.a Preparation of benzene-1,4-disulfonic acid1-[(2,2-diphenyl-ethyl)-amide]4-thiazol-2-ylamide, 10b

The same procedure was used to prepare compound 10a, with the exceptionthat 2-phenylethylamine was used in place of 2,2-diphenylethylamine. MSm/z: 430 (M+1).

Example 3

Example 3 provides methods for testing the efficacy of the compounds ofthe invention.

3.1.4 Cell Line Construction and Maintenance

Human Embryonic Kidney (HEK) cells were transfected with an hSCN3Aconstruct using lipofectamine reagent (Invitrogen), using standardtechniques. Cells stably expressing the hSCN3A constructs wereidentified by their resistance to G-418 (400 μg/ml). Clones werescreened for expression using the whole-cell voltage-clamp technique.

3.2.a Cell Culture

HEK cells stably transfected with hSCN3A were maintained in DMEM mediumsupplemented with 10% heat-inactivated fetal bovine serum and 400 μg/mlG418 sulfate in an incubator at 37° C. with a humidified atmosphere of10% CO₂. For HTS, cells were harvested from flasks by trypsinization andreplated in an appropriate multi-well plate (typically 96 or 384wells/plate) such that confluence would be achieved within 24 hours ofplating. For electrophysiological studies, cells were removed from theculture flask by brief trypsinization and replated at low density ontoglass cover slips. Cells were typically used for electrophysiologicalexperiments within 24 to 72 h after plating.

3.3.a Electrophysiological Recording

Cover slips containing HEK cells expressing hSCN3A were placed in a bathon the stage of an inverted microscope and perfused (approximately 1ml/min) with extracellular solution of the following composition: 138 mMNaCl, 2 mM CaCl₂, 5.4 mM KCl, 1 mM MgCl₂, 10 mM glucose, and 10 mMHEPES, pH 7.4, with NaOH. Pipettes were filled with an intracellularsolution of the following composition: 135 mM CsF, 5 mM CsCl, 2 mMMgCl₂, 10 mM EGTA, 10 mM HEPES, pH 7.3 to 7.4, and had a resistance of 1to 2 mega ohms. The osmolarity of the extracellular and intracellularsolutions was 300 mmol/kg and 295 mmol/kg, respectively. All recordingswere made at room temperature (22-24° C.) using AXOPATCH 200B amplifiersand PCLAMP software (Axon Instruments, Burlingame, Calif.) orPatchXpress 7000 hardware and associated software (Axon Instruments,Burlingame, Calif.).

hSCN3A currents in HEK cells were measured using the whole-cellconfiguration of the patch-clamp technique (Hamill et al., 1981).Uncompensated series resistance was typically 2 to 5 mega ohms and >85%series resistance compensation (50% for PatchXpress) was routinelyachieved. As a result, voltage errors were negligible and no correctionwas applied. Current records were acquired at 20 to 50 KHz and filteredat 5 to 10 KHz.

The voltage-dependence of inactivation was determined by applying aseries of depolarizing prepulses (8 sec long in 10 mV increments) from anegative holding potential. The voltage was then immediately stepped to0 mV to assess the magnitude of the sodium current. Currents elicited at0 mV were plotted as a function of prepulse potential to allowestimation of the voltage midpoint of inactivation (V_(1/2)). Cells werethen voltage clamped at the empirically determined V_(1/2).

Compounds were tested for their ability to inhibit hSCN3A sodiumchannels by activating the channel with a 20 ms voltage step to 0 mVfrom the empirically determined V_(1/2). HEK cells stably transfectedwith hSCN3A were viewed under Hoffman contrast optics and placed infront of an array of flow pipes emitting either control orcompound-containing extracellular solutions. In the cases where datawere generated on the PatchXpress the onboard liquid handling facilityof the instrument was used. All the compounds were dissolved in dimethylsulfoxide to make 10 mM stock solutions, which were then diluted intobath solution to attain the final concentrations desired. The finalconcentration of dimethyl sulfoxide (≦1% dimethyl sulfoxide) was foundto have no significant effect on hSCN3A sodium currents.

3.4.a High-Throughput Screening Assays

Confluent cells in multi-well plates were incubated with a permeantradioactive ion (²²Na, ¹⁴C-guanidinium, etc) for 4-16 hours to allowuptake of the radiotracer. Excess radioactive ions were removed bywashing with prewarmed buffer of the following composition: 138 mM NaCl,2 mM CaCl₂, 5.4 mM KCl, 1 mM MgCl₂, 10 mM glucose, and 10 mM HEPES, pH7.4, with NaOH. Efflux was initiated by addition of buffer containingany necessary chemical activators (e.g., 100 μM veratridine, 10-20 μg/mlLqh scorpion venom, etc.). Various concentrations of test compounds orreference sodium channel blockers were added concurrently with theinitiation of efflux. Efflux was allowed to progress for a definedperiod of time, typically 30-90 minutes, at 37° C. in a humidified 10%CO₂ atmosphere. Stimulated efflux was determined by collecting theextracellular solution and transferring to a multiwell plate forscintillation counting. Residual intracellular radioactivity was alsodetermined by scintillation counting following lysis of the cells in theassay plate. Inhibition of efflux was determined by comparing efflux inthe presence of test compounds to efflux in untreated control cells.

The activity of certain compounds of the present invention is set forthin Table II, below.

TABLE II SCN3A Compound Inhibitory Number NAME Activity 1N-[(2,2-diphenyl)]-ethyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-++++ sulfamide 2N-(3,3-diphenylpropyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]- ++++sulfamide 3N-(3,4-dichloro-phenyl)-ethyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-++++ sulfamide 4N-(trans-2-phenylcyclopropyl)-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-++++ sulfamide 5N-[2-(4-phenoxyl-phenyl)-ethyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-++++ sulfamide 6 Benzene-1,4-disulfonic acid1-{[2-(4-tert-butyl-phenoxy)-ethyl]-amide} 4- ++++[(5-chloro-thiazol-2-yl)-amide] 7 Benzene-1,4-disulfonic acid1-[(5-chloro-thiazol-2-yl)-amide] 4-[(3,3- ++++ dimethyl-butyl)-amide] 84-[4-(3-Chloro-phenoxy)-piperidine-1-sulfonyl]-N-thiazol-2-yl- ++++benzenesulfonamide 9 Benzene-1,4-disulfonic acid1-[(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin- ++++ 2-ylmethyl)-amide]4-thiazol-2-ylamide 104-[4-(4-Chloro-2-fluoro-phenyl)-piperazine-1-sulfonyl]-N-(5-chloro-thiazol-++++ 2-yl)-benzenesulfonamide 11 Benzene-1,4-disulfonic acid1-(4-tert-butyl-benzylamide) 4-thiazol-2-ylamide ++++ 12Benzene-1,4-disulfonic acid 1-{[3-(4-chloro-phenoxy)-propyl]-amide}4-[(5- ++++ chloro-thiazol-2-yl)-amide] 13 Benzene-1,4-disulfonic acid1-({2-[(4-chloro-phenyl)-methyl-amino]-ethyl}- ++++ amide)4-thiazol-2-ylamide 14 Benzene-1,4-disulfonic acid1-{[2-(4-tert-butyl-phenoxy)-2-methyl-propyl]- ++++ amide}4-[(5-chloro-thiazol-2-yl)-amide] 15 Benzene-1,4-disulfonic acid1-[(5-chloro-thiazol-2-yl)-amide] 4-(4- ++++trifluoromethyl-benzylamide) 16 Benzene-1,4-disulfonic acid1-{[2-(4-tert-butyl-phenylamino)-ethyl]-amide} ++++ 4-thiazol-2-ylamide17 Benzene-1,4-disulfonic acid1-{[1-(4-chloro-phenoxy)-cyclobutylmethyl]- ++++ amide}4-thiazol-2-ylamide 18 Benzene-1,4-disulfonic acid1-{[2-(4-chloro-3-methyl-phenoxy)-ethyl]- ++++ amide}4-thiazol-2-ylamide 194-[(S)-2-(4-chloro-phenoxymethyl)-pyrrolidine-1-sulfonyl]-N-thiazol-2-yl-++++ benzenesulfonamide 20 Benzene-1,4-disulfonic acid1-{[1-(4-chloro-2-fluoro-phenoxy)- ++++ cyclobutylmethyl]-amide}4-thiazol-2-ylamide 21 Benzene-1,4-disulfonic acid1-{[1-(4-chloro-phenyl)-cyclobutylmethyl]- ++++ amide}4-thiazol-2-ylamide 22N-[(3,3-diphenyl)]-propyl]-N′-{5-[5-(N-thiazol-2-yl-sulfonamyl)- +++pyridinyl]}-sulfamide 23 4-(3,4-Dichloro-phenyl)-piperazine-1-sulfonicacid [4-(thiazol-2- +++ ylsulfamoyl)-phenyl]-amide 24Benzene-1,4-disulfonic acid 1-[(2,2-diphenyl-ethyl)-amide] 4-thiazol-2-+++ ylamide 25 2,5-Difluoro-benzene-1,4-disulfonic acid1-{[2-(3,4-dichloro-phenyl)-ethyl]- +++ amide} 4-thiazol-2-ylamide 26N-(5-chloro-thiazol-2-yl)-4-[3-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-+++ azetidine-1-sulfonyl]-benzenesulfonamide 27 Benzene-1,4-disulfonicacid 1-{[2-(4-chloro-phenyl)-ethyl]-amide} 4-thiazol- +++ 2-ylamide 28N-(5-chloro-thiazol-2-yl)-4-[3-(3,4-dichloro-benzylidene)-azetidine-1-+++ sulfonyl]-benzenesulfonamide 294-[4-(4-Chloro-benzyl)-piperidine-1-sulfonyl]-N-thiazol-2-yl- +++benzenesulfonamide 30 Benzene-1,4-disulfonic acid 1-cycloheptylamide4-thiazol-2-ylamide +++ 31 Benzene-1,4-disulfonic acid1-{[2-(4-tert-butyl-phenylamino)-2-methyl- +++ propyl]-amide}4-thiazol-2-ylamide 32 Benzene-1,4-disulfonic acid1-{[(R)-2-(4-chloro-phenoxy)-propyl]-amide} 4- +++[(5-chloro-thiazol-2-yl)-amide] 33 Benzene-1,4-disulfonic acid1-{[(S)-2-(4-chloro-phenoxy)-propyl]-amide} 4- +++[(5-chloro-thiazol-2-yl)-amide] 34 Benzene-1,4-disulfonic acid1-{[2-(4-chloro-2-fluoro-phenoxy)-ethyl]- +++ amide} 4-thiazol-2-ylamide35 Benzene-1,4-disulfonic acid1-{[2-(4-tert-butyl-phenoxy)-ethyl]-methyl- +++ amide}4-thiazol-2-ylamide 364-[3-(3-Chloro-phenoxymethyl)-azetidine-1-sulfonyl]-N-thiazol-2-yl- +++benzenesulfonamide 37 Benzene-1,4-disulfonic acid1-(3-chloro-4-methoxy-benzylamide) 4-thiazol- +++ 2-ylamide 38Benzene-1,4-disulfonic acid 1-{[1-(4-tert-butyl-phenoxy)- +++cyclopentylmethyl]-amide} 4-thiazol-2-ylamide 39 Benzene-1,4-disulfonicacid 1-{[2-(4-chloro-phenyl)-2-methyl-propyl]- +++ amide}4-thiazol-2-ylamide 40 Benzene-1,4-disulfonic acid1-(3-fluoro-5-trifluoromethyl-benzylamide) 4- +++ thiazol-2-ylamide 41Benzene-1,4-disulfonic acid 1-{[2-(5-chloro-thiophen-2-yl)-ethyl]-amide}4- +++ thiazol-2-ylamide 42 2-Fluoro-benzene-1,4-disulfonic acid4-[(3,3-dimethyl-butyl)-amide] 1- +++ thiazol-2-ylamide 43N-[2-(2-chloro-phenoxyl)-ethyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)-phenyl]-++ sulfamide 44 Benzene-1,4-disulfonic acid1-[(2-cyclohexyl-ethyl)-amide] 4-thiazol-2- ++ ylamide 45N-[(2,2-diphenyl)]-ethyl]-N′-{2-[5-(N-thiazol-2-yl-sulfonamyl)-pyridinyl]}- +sulfamide 46N-[2-(4-tetrahydro-pyranyl]-ethyl]-N′-[4-(N-thiazol-2-yl-sulfonamyl)- +phenyl]-sulfamide 47 Benzene-1,4-disulfonic acid1-(methyl-phenethyl-amide) 4-thiazol-2-ylamide + Key: + indicates IC50 >1 μM; ++ indicates 1 μM > IC50 > 0.5 μM; +++ indicates 0.5 μM > IC50 >0.1 μM; ++++ indicates IC50 < 0.1 μM

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention.

All patents, patent applications, and other publications cited in thisapplication are incorporated by reference in their entirety.

1-11. (canceled)
 12. A compound according to Formula I:

wherein A is

wherein R¹⁸ and R¹⁹ are each independently selected from H,unsubstituted alkyl or phenyl; or R¹⁸ and R¹⁹, together with the carbonatoms to which they are attached, are joined to form an unsubstitutedcycloalkyl; the subscript t is an integer selected from 1 to 4; J is amember selected from phenyl, phenoxy, phenylamino, cyclohexyl,cycloheptyl, tetrahedropyranyl, benzodioxanyl, thiophenyl, pyridinoxy orhomoalkyl, wherein the aromatic portion of which is optionallysubstituted with from one to two members selected from phenoxy,homoalkyl, homoalky-oxy, halogen or halo-homoalkyl; R⁶ is H or; R⁶ andR¹⁸ together with the atoms to which R⁶ and R¹⁸ are attached, areoptionally joined to form an azetidinyl, piperidinyl, pyrrolidinyl orpiperazinyl moiety; B is a member selected from:

wherein R²⁰ and R21 are members independently selected from H, halogen,or homoalkyl; or a pharmaceutically acceptable salt thereof.
 13. Thecompound of claim 12, having the formula selected from the groupconsisting of:


14. A pharmaceutical formulation comprising the compound of claim 12 ora pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.
 15. The compound of claim 12, wherein R²⁰ and R²¹are each independently selected from H or halogen.
 16. The compound ofclaim 15, wherein R²⁰ and R²¹ are each independently selected from H orhalogen; R¹⁸ and R¹⁹ are each independently selected from H, phenyl orunsubstituted alkyl; or R¹⁸ and R¹⁹ together with the carbon atoms towhich they are attached, are joined to form a cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl ring; and J is selected from phenyl, phenoxy,phenylamino, cyclohexyl, cycloheptyl, tetrahedropyranyl, benzodioxanyl,thiophenyl, pyridinoxy or homoalkyl wherein the aromatic portion ofwhich is optionally substituted with from one to two membersindependently selected from halogen, methyl, trifluoromethyl, ethyl,t-butyl, or methoxy.
 17. The compound of claim 16, wherein J is phenyl,phenyloxy, phenylamino, pyridinoxy or benzo[1,4]dioxin-2-yl, wherein thearomatic portion of which is optionally substituted with from one to twomembers independently selected from halogen, methyl, trifluoromethyl,ethyl, t-butyl, or methoxy.
 18. The compound of claim 13, wherein R²⁰and R²¹ are each independently selected from H or halogen; R¹⁸ and R¹⁹are each independently selected from H, phenyl or unsubstituted alkyl;or R¹⁸ and R¹⁹ together with the carbon atoms to which they areattached, are joined to form a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl ring; J is selected from phenyl, phenoxy, phenylamino,cyclohexyl, cycloheptyl, tetrahedropyranyl, benzodioxanyl, thiophenyl,pyridinoxy or homoalkyl, wherein the aromatic portion of which isoptionally substituted with from one to two members independentlyselected from halogen, methyl, trifluoromethyl, ethyl, t-butyl, ormethoxy.
 19. The compound of claim 18, wherein J is phenyl, optionallysubstituted with from one to two members independently selected fromhalogen, methyl, trifluoromethyl, ethyl, t-butyl, or methoxy.
 20. Thecompound of claim 12, wherein A is a member selected from:

wherein J is selected from the group consisting of phenyl, phenoxy,phenylamino, cyclohexyl, cycloheptyl, tetrahedropyranyl, benzodioxanyl,thiophenyl, pyridinoxy or homoalkyl, wherein the aromatic portion ofwhich is optionally substituted with from one to two membersindependently selected from the group consisting of halogen, methyl,trifluoromethyl, ethyl, t-butyl and methoxy.
 21. The compound of claim20, wherein J is selected from the group consisting of phenyl,phenyloxy, phenylamino and pyridinyloxy, wherein aromatic portion ofwhich is optionally substituted with from one to two membersindependently selected from the group consisting of halogen, methyl,trifluoromethyl, ethyl, t-butyl and methoxy.
 22. The compound of claim21, wherein J is phenyl optionally substituted with from one to twomembers independently selected from the group consisting of halogen,methyl, trifluoromethyl, ethyl, t-butyl and methoxy.
 23. The compound ofclaim 22, wherein J is chlorophenyl, fluorophenyl, dichlorophenyl,difluorophenyl, chlorofluorophenyl, trifluoromethylfluorophenyl,trifluoromethylchlorophenyl, t-butylchlorophenyl, t-butylfluorophenyl,methylchlorophenyl, methylfluorophenyl, methoxychlorophenyl ormethoxyfluorophenyl.
 24. The compound of claim 21, wherein J is phenoxyoptionally substituted with from one to two members independentlyselected from the group consisting of halogen, methyl, trifluoromethyl,ethyl, t-butyl and methoxy.
 25. The compound of claim 24, wherein J ischlorophenoxy, fluorophenoxy, dichlorophenoxy, difluorophenoxy,chlorofluorophenoxy, trifluoromethylfluorophenoxy,trifluoromethylchlorophenoxy, t-butylchlorophenoxy,t-butylfluorophenoxy, methylchlorophenoxy, methylfluorophenoxy,methoxychlorophenoxy or methoxyfluorophenoxy.
 26. The compound of claim21, wherein J is phenylamino optionally substituted with from one to twomembers independently selected from the group consisting of halogen,methyl, trifluoromethyl, ethyl, t-butyl and methoxy.
 27. The compound ofclaim 26, wherein J is chlorophenylamino, fluorophenylamino,dichlorophenylamino, difluorophenylamino, chlorofluorophenylamino,trifluoromethylfluorophenylamino, trifluoromethylchlorophenylamino,t-butylchlorophenylamino, t-butylfluorophenylamino,methylchlorophenylamino, methylfluorophenylamino,methoxychlorophenylamino or methoxyfluorophenylamino.
 28. The compoundof claim 21, wherein J is pyridinyloxy optionally substituted with fromone to two members independently selected from the group consisting ofhalogen, methyl, trifluoromethyl, ethyl, t-butyl and methoxy.
 29. Thecompound of claim 28, wherein J is selected from chloropyridinyloxy,fluoropyridinyloxy, dichloropyridinyloxy, difluoropyridinyloxy,chlorofluoropyridinyloxy, trifluoromethylfluoro pyridinyloxy,trifluoromethylchloropyridinyloxy, t-butylchloropyridinyloxy,t-butylfluoropyridinyloxy, methylchloropyridinyloxy,methylfluoropyridinyloxy, methoxychloropyridinyloxy ormethoxyfluoropyridinyloxy.
 30. A compound having the formula:

wherein J is selected from phenyl, phenoxy, phenylamino, cyclohexyl,cycloheptyl, tetrahedropyranyl, benzodioxanyl, thiophenyl, pyridinoxy orhomoalkyl, wherein the aromatic portion of which is optionallysubstituted with from one to two members selected from phenoxy,homoalkyl, homoalky-oxy, halogen or halo-homoalkyl; B is a memberselected from:

R²⁰ and R²¹ are members independently selected from H, halogen orhomoalkyl.
 31. The compound of claim 30, wherein J is phenyl optionallysubstituted with from one to two members independently selected from thegroup consisting of halogen, methyl, trifluoromethyl, ethyl, t-butyl andmethoxy.
 32. The compound of claim 31, wherein J is chlorophenyl,fluorophenyl, dichlorophenyl, difluorophenyl, chlorofluorophenyl,trifluoromethylfluorophenyl, trifluoromethylchlorophenyl,t-butylchlorophenyl, t-butylfluorophenyl, methylchlorophenyl,methylfluorophenyl, methoxychlorophenyl or methoxyfluorophenyl.
 33. Thecompound of claim 12, wherein A is a member selected from:

wherein J is selected from the group consisting of phenyl, phenoxy,phenylamino, cyclohexyl, cycloheptyl, tetrahedropyranyl, benzodioxanyl,thiophenyl, pyridinoxy or homoalkyl, wherein the aromatic portion ofwhich is optionally substituted with from one to two membersindependently selected from the group consisting of halogen, methyl,trifluoromethyl, ethyl, t-butyl and methoxy.
 34. The compound of claim33, wherein J is selected from the group consisting of methyl, ethyl,propyl, 3,3-dimethylbutyl, phenyl, phenyloxy and phenylamino, whereinthe phenyl moiety is optionally substituted with from one to two membersindependently selected from the group consisting of halogen, methyl,trifluoromethyl, ethyl, t-butyl and methoxy.
 35. The compound of claim34, wherein J is phenyl optionally substituted with from one to twomembers independently selected from the group consisting of halogen,methyl, trifluoromethyl, ethyl, t-butyl and methoxy.
 36. The compound ofclaim 35, wherein J is chlorophenyl, fluorophenyl, dichlorophenyl,difluorophenyl, chlorofluorophenyl, trifluoromethylfluorophenyl,trifluoromethylchlorophenyl, t-butylchlorophenyl, t-butylfluorophenyl,methylchlorophenyl, methylfluorophenyl, methoxychlorophenyl ormethoxyfluorophenyl.
 37. The compound of claim 34, wherein J is phenoxyoptionally substituted with from one to two members independentlyselected from the group consisting of halogen, methyl, trifluoromethyl,ethyl, t-butyl and methoxy.
 38. The compound of claim 37, wherein J ischlorophenoxy, fluorophenoxy, dichlorophenoxy, difluorophenoxy,chlorofluorophenoxy, trifluoromethylfluorophenoxy,trifluoromethylchlorophenoxy, t-butylchlorophenoxy,t-butylfluorophenoxy, methylchlorophenoxy, methylfluorophenoxy,methoxychlorophenoxy or methoxyfluorophenoxy.
 39. The compound of claim34, wherein J is phenylamino optionally substituted with from one to twomembers independently selected from the group consisting of halogen,methyl, trifluoromethyl, ethyl, t-butyl and methoxy.
 40. The compound ofclaim 39, wherein J is chlorophenylamino, fluorophenylamino,dichlorophenylamino, difluorophenylamino, chlorofluorophenylamino,trifluoromethylfluorophenylamino, trifluoromethylchlorophenylamino,t-butylchlorophenylamino, t-butylfluorophenylamino,methylchlorophenylamino, methylfluorophenylamino,methoxychlorophenylamino or methoxyfluorophenylamino
 41. The compound ofclaim 12, wherein J is benzo[1,4]dioxin-2-yl, wherein the phenyl isoptionally substituted with from one to two members independentlyselected from halogen, methyl, trifluoromethyl, ethyl, t-butyl, ormethoxy.
 42. The compound of claim 41, wherein J is selected from thegroup consisting of chlorobenzo[1,4]dioxin-2-yl,fluorobenzo[1,4]dioxin-2-yl, dichlorobenzo[1,4]dioxin-2-yl,difluorobenzo [1,4]dioxin-2-yl, chlorofluorobenzo[1,4]dioxin-2-yl,trifluoromethylfluorobenzo[1,4]dioxin-2-yl,trifluoromethylchlorobenzo[1,4]dioxin-2-yl,t-butylchlorobenzo[1,4]dioxin-2-yl, t-butylfluorobenzo[1,4]dioxin-2-yl,methylchlorobenzo[1,4]dioxin-2-yl, methylfluorobenzo[1,4]dioxin-2-yl,methoxychlorobenzo[1,4]dioxin-2-yl andmethoxyfluorobenzo[1,4]dioxin-2-yl.
 43. The compound of claim 12,wherein the compound is selected from the group consisting of:N-[(3,3-diphenyl)]-propyl]-N′-{5-[5-(N-thiazol-2-yl-sulfonamyl)-pyridinyl]}-sulfamide;andN-[(2,2-diphenyl)]-ethyl]-N′-{2-[5-(N-thiazol-2-yl-sulfonamyl)-pyridiny-1]}-sulfamide.